Except for men presenting with the most advanced stages of prostate cancer, there is general agreement that most men — the vast majority — diagnosed with this disease will die of cardiac complications … and not from prostate cancer. When the association of testosterone suppression and cardiac death is assessed in large studies, studies not specifically focusing on cardiac issues, there is controversy questioning this association. But even in these analyses the risk of a cardiac complication is increased by about 10% or more for users of androgen deprivation therapy (ADT) vs non-users.
However, in meta-analyses of large observational studies that permit consideration of types of androgen suppression, duration, patient age, and comorbidity — especially the extent pre-ADT cardiac disease, the association of ADT with cardiovascular disease (CVD) is strong. The incidence of ischemic heart disease, congestive heart failure, myocardial infarction, stroke, and cardiovascular mortality (CVM) in those men with pre-ADT cardiovascular disease is markedly increased.
The essential quest is to properly evaluate the use of ADT in consideration of the benefit/loss equation. This may be best served in some instances by avoiding ADT altogether, a decision that may be challenging for a clinician to feel comfortable with acknowledging the understandable urge to respond to a rising PSA. An important consideration for reducing the cardiovascular risk may be choosing the best agent for androgen suppression. Overriding these details is the clear imperative for the prescribing physician to review a man’s cardiac history and assess his cardiac risk factors before commencing ADT.
The plausibility of a causal association between testosterone (T) suppression and cardiovascular disease (CVD) and cardiovascular mortality (CVM) is strengthened by acknowledging the biologic consequences of a T lowered to subcastrate levels (20 – 30 ng/dL). Metabolic aberrations associated with castrate T levels include: decreased insulin sensitively and overt diabetes, hypertension, elevation of cholesterol and low-density lipoprotein, abdominal obesity, increasing arterial wall thickness, and proinflammatory and prothrombotic states, all of which predispose to cardiovascular disease.
A normal T level may actually exert a cardioprotective effect and this may be interrupted by ADT. Gonadotropin releasing hormone receptors (GnRHr) have been identified in cardiac muscle and their inhibition may lead to lower cardiac contractility ( Conteduca et al. Crit Rev. Oncol Hematol. 86 2013 ).
One of the puzzling questions was what mechanism might explain heart attacks occurring so early — within 6 months – of starting Lupron. A potential answer seems to be indicated in “Treatment with a GnRH receptor agonist but not with the GnRH antagonist degarelix, induces atherosclerotic plaque instability in ApoE(-/-) mice. The study found that within 4 weeks of Lupron treatment the mooring of stable plaques within the arteries was disrupted.
Their conclusion: Destabilizing of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH agonists,” Knutsson et al. Scientific Reports May 18, 2016.
On the basis of these concerns, in 2010 the FDA issued a safety warning regarding GnRH agonists, i.e., Lupron, Zoladex, and Eligard, cautioning about the increased risk of diabetes, heart attack, sudden cardiac death, and stroke associated with ADT.
- THE FINDINGS OF TWO MAJOR ARTICLES ON THE CARDIOVASCULAR COMPLICATIONS OF ADT:“Risk and Timing of Cardiovascular Disease after Androgen-Deprivation Therapy in Men with Prostate Cancer,” O’Farrell et al. (Kings College London, School of Medicine), Journal of Clinical Oncology. March 2015.
This Swedish study “investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched PCa-free comparison cohort.”
- Antiandrogens (i.e., Casodex and Flutamide) were used in 10,656 men
- GnRH agonists in 26,959 and
- Surgical orchiectomy in 3747
The indication for ADT was a rising PSA after primary therapy or the initial use of ADT without primary therapy. The men were stratified as to risk categories, age, duration of ADT, the number of previous CVD events, and stratified as to the extent of comorbidities, such as myocardial infarction, congestive heart failure, peripheral vascular disease, and cerebrovascular, dementia, chronic pulmonary disease, and diabetes. Having two or more of these conditions should raise concern. (J Chron Dis Vol. 40, 1987)
The major findings:
- CVD was increased in GnRH agonist users 21% compared to non-ADT users.
- CVD risk was highest — a 90% increased risk — during the first 6 months of ADT for those who had experienced two or more cardiovascular events within a year before therapy.
- Orchiectomy was associated with a 16% increase in risk of CVD.
- Men on antiandrogens (AA) were at a reduced risk — by 13% — compared to non-ADT users.
“There should be solid indication for use of ADT so that the perceived benefit outweighs possible harm. This is particularly important in men with a recent history of CVD.”
2. “Androgen Deprivation Therapy for Prostate Cancer Is Associated with Cardiovascular Morbidity and Mortality: A Meta-Analysis of Population-Based Observational Studies,” Zhao et al., (Tianjin, China) PLoS ONE (Public Library of Science) Sept 2014.
The major findings:
After identifying 836 unique articles on the subject, strict selection criteria yielded 6 studies suitable for evaluating the association of ADT (with GnRH agonists) with CVD. Based on 129,802 ADT users compared to 166,605 controls the incidence of CVD was increased 19%. The combination of a GnRH agonist with an antiandrogen increased CVD 46%. Neither AA alone nor orchiectomy increased CVD incidence.
The evaluation of CVM was based on 119,625 ADT users compared to 150,974 controls. The incidence of CVM in men using GnHR agonists alone was increased 36%. When combined with an AA the increase was 44%. There was no increase in CVM when antiandrogens were used alone.
GnRH agonists alone and combined with an antiandrogen increase the risk of cardiovascular disease and mortality. This association underlines the need to “define populations for whom benefits from ADT outweigh risks and to develop strategies to prevent ADT-related cardiovascular events.”
STUDIES COMPARING THE RISK OF CARDIOTOXICITY OF ADT: GnRH ANTAGONIST (degarelix) versus GnRH AGONISTS ( i.e. Lurpon, Zoladex, Eligard )
- Research on this important issue was reported in “Risk of cardiovascular events with degarelix versus leuprolide [Lupron] after biochemical relapse of prostate cancer: Exploratory analysis of a randomized controlled trial,” Higano, Crawford, Klotz et al. Journal of Clinical Oncology, March 1 Supplement, 2015.
Their study of 175 men compared the incidence of non-fatal CV events in men with prostate cancer having pre-existing CV disease. Of interest, in the group of men in their mid-70’s 35% had a history of CVD at study entry. The arms were well matched for both cardiac and prostate cancer risk factors.
Their findings: “During the observation period [of one year] a subsequent CV event occurred in 3 (3.4%) men treated with degarelix and 8 (14.5%) treated with leuprolide ….”
2. At ASCO Genitourinary Symposium 2016, abstract 232, a German group reported on cardiovascular events in three groups of cancer patients: 4436 men treated with GnRH agonists; 133 with the antagonist; and 37, 367 who received no ADT.
Myocardial infarction or ischemic stroke occurred in 6.27%, 3.76%, and 4.62% in the agonist, antagonist, and no-ADT group respectively. Cardiovascular events were seen in 11.27%, 7.52%, and 8.38% of men in the agonist, antagonist, and no-ADT groups.
Their finding: “Our results indicate that ADT with GnRH antagonists is associated with fewer CV events in PCa patients than treatment with GnRH agonists.”
3. In European Urology, March 1014, Albertsen, Klotz, Tombal et al. reported the results of six phase 3 prospective randomized studies (including the study cited above by Higano): “Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist.”
Their analysis was based on 837 receiving an agonist and 1491 receiving degarelix. Treatment was administered for 1 year in 72% of patients, and for 3 – 7 months in the other men. The study end points were death from any cause or a new occurrence of a cardiac event during 1 year of observation. Study entry required an excellent or good performance rating.
As also noted in the Higano article, in this age group, i.e. in their mid-70 years, a history of cardiovascular disease was already very prevalent in 30% including: myocardial ischemia, 11%; myocardial infarction, 7%; coronary artery disease, 8%; stroke, 4%; angina, 3.3%; and history of coronary artery bypass, 3.1%.
Their findings: During the year there was a 40% decrease in death or a new cardiac event favoring degarelix compared to a GnRH agonist.
“No difference in the incidence of either death from any cause or the incidence of cardiac events was seen among men who had no preexisting CV disease at baseline.”
The biologic explanation for the claimed superiority of a GnRH antagonist over an agonist is unclear. Both agents lower pituitary secretion of luteinizing hormone (LH) resulting in T suppression. However the antagonist also reduces pituitary secretion of follicle-stimulating hormone (FSH) thought to exert a protective effect on blood vessel wall function.
Their conclusion: “Our study [finds] that among men with preexisting CV disease, those receiving GnRH agonists had twice the incidence of cardiac events when compared to men receiving a GnRH antagonist.
BOTTOM LINE: Although still a controversial issue, multiple studies report persuasive evidence for an adverse association of ADT and cardiovascular toxicity. This association is especially strong in men with preexisting CV disease. The adverse consequence of ADT may be lessened by using a GnRH antagonist as opposed to an agonist. Considering the common prevalence of preexisting CV disease, a thorough screening of men for CV risk factors or prior CV events is essential. With this information a clinician has an opportunity to attempt to modify risk factors, and in some cases decide to avoid ADT altogether.